Helicobacter pylori is a spiral, short rod-shaped, gram-negative bacterium having monopolar and several sheathed flagella. The bacteria are detected both in the gastric mucous layer and on the surface of gastric epithelial cells.
The fact that spiral bacteria live on and in a gastric mucosa has been observed by many researchers. Firstly in 1983, Marshall et al. succeeded in cultivating spiral bacteria through isolation of the same from a gastric mucosa. The bacterium was originally named Campylobacter pylori since its shapes and biochemical characteristics are analogous to those of the genus Campylobacter which is one of known enteritis-causing bacterial genera. However, later bacterial taxonomic researches established a new independent genus including the bacterium, and the bacterium was renamed Helicobacter pylori. In 1984, Marshall et al. detected the bacteria at high percentage from patients suffering from peptic ulcer such as gastric and duodenal ulcers and chronic gastritis, and suggested relevance of the bacteria to occurrence and recurrence of these diseases. As conventional remedies against peptic ulcer, medical treatments with gastric secretion inhibitors have been utilized; advent of H.sub.2 -blocker such as cimetidine and proton-pump inhibitor such as omeprazole enhanced the cure rate up to 80-90%. However, it has been reported that about 50% of patients healed with administration of anti-ulcer agents have relapse or recurrence of ulcers within twelve months and that, particularly, patients healed with gastric secretion inhibitors such as H.sub.2 -blockers and proton-pump inhibitors have relapse rate of as high as 70-90%. Thus, prevention of the relapse or recurrence is one of greatest problems in the treatment.
There have, however, been recently increasingly reported that removal of Helicobacter pylon (hereinafter referred to as Hp) with an antibacterial agent will decrease ulcer relapse rate [see for example SAISHIN-IGAKU: Vol. 44, No. 2, pp. 295-302, (1989)]; and, in February 1994, NIH in U. S. A. advised necessity of eradicating Hp in the treatment of peptic ulcer. Hp-eradication agents used nowadays are for example antibiotics and bismuth preparations. Antibiotics are not suitable for long-term use since they may also affect other intestinal bacteria and may cause advent of resistant bacteria. Treatment with bismuth preparations is rather problematic since the bismuth preparations are weak in antibacterial activity and may cause vomiting, diarrhea and/or side effects on central nervous system.
Anti-ulcer agents with antibacterial activities against Hp have been proposed for example in Japanese Patent Provisional Publication (Kokai) Nos. 4-364160 and 5-117268; however, none of the proposed agents have sufficient selectivity and antibacterial activity. Under such circumstances, there have been demand on development of preparations having higher selectivity on Hp as well as having higher antibacterial activity against Hp in the treatment of peptic ulcer and chronic gastritis with Hp infection.
Recently, quinoline-4(1H)-thione derivatives were found to have antibacterial activity selectively against Hp and have been suggested as antibacterial agents against Hp (WO 96/11187). However, there has been still room for inprovement in strength of antibacterial activity.
In order to overcome the above-mentioned problems, we, the inventors carried out intensive studies to find that quinoline sulfide derivatives of the above-mentioned formula I which are obtained by modifying thione functional group of quinoline-4(1H)-thione derivatives have antibacterial activity selectively against Hp and superior to that of the above-mentioned quinoline-4(1H)-thione derivatives, thus accomplishing the present invention.
Known quinoline sulfide derivatives similar to the compounds of the present invention are benzyl sulfide derivatives of quinoline disclosed in Japanese Patent Provisional publication (Kokai) No. 1-246264 and U.S. Pat. No. 5,296,484; disclosed in them is bactericidal effect against botanically pathogenic bacteria or acari- or insecticidal effect. Analogical derivatives are also disclosed in Synthesis (1): 56 (1995). However, no reports have been made on antibacterial effect of these quinoline sulfide derivatives against Hp at all. Provision of quinoline sulfide derivatives as antibacterial agent against Hp is originally proposed in the present application.